Tumor suppressor genes encode proteins that inhibit progression through the cell cycle, thereby inhibiting cell growth and/or cell division. When DNA damage is detected in a cell, tumor suppressors prevent the cell from continuing to multiply until the damaged DNA is repaired. Alternatively, if the DNA cannot be repaired, they may signal the cell to undergo apoptosis (programmed cell death) in order to prevent the damaged DNA from being passed on to the daughter cells. Tumor suppressors therefore play a critical role in preventing the onset of uncontrolled cell growth, or neoplasia.
Most tumor suppressor genes are recessive, and the development of a tumor usually requires two separate mutational events. Only when both alleles of a tumor suppressor gene are lost or damaged is the control that it exerted on cell growth lost, thereby allowing neoplasia. One of these mutational events may occur in the germline and be inherited; the second then occurs somatically. Alternatively, the two mutational events may occur only in the somatic cell of an individual.
Two of the best-characterized tumor suppressor genes are the retinoblastoma (Rb) and p53 genes. Mutations in both alleles of the Rb gene results in the development of retinoblastoma, a malignant tumor of the retina which appears in infants and young children, and is also involved in the development of bone, bladder, small cell lung, and breast tumors. The Rb gene codes for the nuclear protein pRB that functions as a major inhibitor of the cell cycle.
The p53 gene is mutated in approximately half of the human tumors, and is therefore believed to be the most frequently mutated gene in human neoplasias. Mutated versions of p53 have been found in a variety of tumors, including those of the colon, brain, lung, and breast, and in leukemias and osteosarcomas.
Recently, a new tumor suppressor gene family, the ING family, has been identified (Garkavtsev et al., Nat. Genet. 14:415-420, 1996; Gunduz et al., Cancer Res. 60:3143-3146, 2000; Saito et al., J. Hum. Genet. 45:177-181, 2000; Jager et al., Cancer Res. 59:6197-204, 1999). Members include ING1 (which has three alternatively spliced forms: p47ING1a, p33ING1b and p24ING1c), and ING2.
p33ING1 shares many biological functions with p53. It has been reported to mediate growth arrest, senescence, apoptosis, anchorage-dependent growth, and chemosensitivity. Neither p53 or p33ING1 can inhibit cell growth on its own and specific biological functions, such as cell-cycle arrest and apoptosis, have been shown to be dependent on the activity of both of these proteins. Mutations in p33ING1 have been demonstrated in neuroblastoma cells and esophageal squamous cell carcinomas (Garkavtsev et al., Nat. Genet. 14:415-420, 1996; Chen et al., Cancer Res. 61:4345-4349, 2001). Decreased p33ING1 expression in esophageal squamous cell carcinomas (Chen et al., Cancer Res., 61:4345-4349, 2001) and in lymphoid malignancies (Ohmori et al., Am. J. Hematol. 62:118-119, 1999) have also been described.
Relatively few tumor suppressor genes have been identified, given the number of recessive mutations that have been associated with neoplasias. Since tumor suppressor genes may function in a cell-specific manner, the few already identified may not be useful in treating all neoplasias. There is therefore a continuing need to identify and isolate other tumor suppressor genes as diagnostic and therapeutic agents for identification and treatment of neoplasias and other diseases.